1. Field of the Invention
The present invention relates to a method for converting farnesol to nerolidol in the presence of alpha-bisabolol. Thus, the present invention relates to a method of depletion of farnesol from mixtures containing farnesol and alpha-bisabolol.
2. Description of Related Art
Natural alpha-bisabolol is an important constituent of the essential oil of the chamomile species Chamomilla recutita. Alpha-bisabolol is used in cosmetic and pharmaceutical applications owing to its skin-calming and anti-inflammatory properties. Furthermore, alpha-bisabolol is used as an odoriferous substance in the perfume industry.
Whereas the systematic cultivation of medicinal and spice plants such as chamomile is becoming increasingly important owing to a growing demand for “renewable raw materials”, the limited natural resources have at the same time led to the search for and development of methods of producing synthetic products.
Synthetic “alpha-bisabolol” is usually a diastereomeric racemate of equal proportions of (+/−)-alpha-bisabolol and (+/−)-epi-alpha-bisabolol. These four enantiomers (+)-epi-alpha-bisabolol, (−)-alpha-bisabolol, (+)-epi-alpha-bisabolol, (−)-epi-alpha-bisabolol possess a structure according to formula A

in which wavy lines stand, in each case independently of one another, for an S- or R-configuration on the associated carbon atom. The compounds of formula A are designated together in the present text with the term alpha-bisabolol.
Owing to their structural similarity to alpha-bisabolol, the sesquiterpenes nerolidol (formula B) and farnesol (formula C), in which wavy lines stand in each case independently of one another for an S- or R-configuration on the associated carbon atom, present themselves as starting materials for industrial synthesis.

Thus, a great many methods and processes have been described in the past for the production of alpha-bisabolol starting from nerolidol or farnesol.
The first catalytic cyclization of farnesol was described in 1913, when it was observed that on carrying out a reaction in the presence of potassium hydrogen sulfate, in addition to the expected hydrocarbons, some mono- and bicyclic compounds were also found [Chem. Ber. 46, 4024 (1913)]. Later works then identified these cyclic compounds as compounds of the bisabolene and cadalene class.
In 1925 it was shown for the first time that starting from nerolidol, by acid catalysis, products such as farnesene, bisabolene and alpha-bisabolol are obtained [Hely. Chim. Acta 8, 259 (1925)]. It was shown, in particular, that by adding acetic anhydride, then reacting with acetic acid/sulfuric acid or formic acid at room temperature, followed by saponification, nerolidol yields a mixture that comprises alpha-bisabolol and farnesol.
In 1968, Gutsche reported [Tetrahedron 24, 859] on the acid-catalyzed cyclization of farnesol and nerolidol. Starting from farnesol or nerolidol, first by reacting with formic acid, the corresponding formates were obtained, which were then saponified in a second step to the alcohols. Following this procedure, however, mixtures of substances are formed, which contain farnesol as well as alpha-bisabolol. Subsequent purification by distillation to highly-enriched alpha-bisabolol proves difficult, especially because alpha-bisabolol and cis,cis-farnesol have almost identical boiling points and the mixtures of substances obtained by the procedure described contain up to 10% of cis,cis-farnesol.
Further syntheses of alpha-bisabolol were described by Ruzicka et al. [Hely. Chim. Acta 15, 3, (1932)] and by Manjarrez et al. [J. Org. Chem. 31, 348, (1966)]. The acid-catalyzed cyclization in the presence of formic acid in pentane or AlCl3 in ether [Tetrahedron Lett. 1972, 2455], KHSO4 [J. Org. Chem. 34, 3789, (1969)] and BF3-etherate in methylene chloride [Chem. Lett. 1972, 263] was also described.
Uneyama et al. report on an electrochemical method of preparation [Chem. Lett. 1984, 529], and the production of DL-bisabolol from DL-nerolidol is also reported. Whereas the methods presented previously, starting from nerolidol, rarely led to alpha-bisabolol yields over 30%, with electrochemical methods yields of up to 52% were obtained.
WO 2004/033401 discloses a method of producing alpha-bisabolol, in which nerolidol is reacted in a step with a mixture consisting of a ketone, a sulfonic acid and perchloric acid. This method is characterized in that, among other things, it leads to an especially pure alpha-bisabolol and in particular the (+), (−) or (+/−)-farnesol that formed as a by-product in the methods described previously in a yield of up to 40%, only formed in relatively low concentrations. However, the use of perchloric acid is problematic on grounds of safety.
The use of perchloric acid, which is critical from the standpoint of safety, is avoided in the method known from DE 10 2005 053 338 for production of alpha-bisabolol, comprising the reaction of farnesol or nerolidol or mixtures of farnesol and nerolidol in the presence of a ketone, a sulfonic acid and another strong acid, except perchloric acid.
US 2008/0269530 A1 discloses a method of producing alpha-bisabolol, comprising the reaction of farnesol in the presence of a ketone, a sulfonic acid and another strong acid. The resulting product mixture contains alpha-bisabolol and its dehydration products as main components. After working up the reaction mixture, farnesol is still only present in low concentrations.
Syntheses starting from farnesol supply the desired alpha-bisabolol, but only in lower yields compared to the syntheses starting from nerolidol.
A feature that the known methods of production of alpha-bisabolol have in common is that farnesol is also formed regularly, in varying amounts. However, the presence of farnesol in product mixtures along with alpha-bisabolol is undesirable, because farnesol is described as having allergenic potential, which in particular makes its use in cosmetic products problematic. In the development of cosmetic products, not only the cosmetic properties are of interest—it is of course also necessary to ensure that the ingredients are harmless to people and the environment. Improved toxicological, ecotoxicological and dermatological properties contribute to the value of a new product. Dermatologically, a cosmetic product should not have any skin-irritant, sensitizing and/or photosensitizing properties. In that sense, the presence of farnesol in cosmetic products is increasingly being perceived as problematic.
It was mentioned above that the separation of alpha-bisabolol and farnesol by distillation is difficult in particular because alpha-bisabolol and cis,cis-farnesol have almost identical boiling points. If it is nevertheless necessary for product mixtures that also comprise a notable proportion of farnesol along with the desirable alpha-bisabolol to be separated by distillation, attainment of at least a certain level of success requires such long thermal loading that there is considerable occurrence of side reactions and especially decomposition of the previously synthesized compounds. In addition, the conventional separation of alpha-bisabolol and farnesol by distillation only gives farnesol of low purity, which is not suitable for direct further use, and especially not as an educt for the synthesis of alpha-bisabolol.
The removal of farnesol from mixtures with alpha-bisabolol by esterification is described in U.S. Pat. No. 7,399,880 B2. The method avoids the problem of separation by distillation, by selective transesterification of the farnesol contained in the mixture with a carboxylic acid ester in the presence of a transesterification catalyst. The farnesyl esters thus obtained now have boiling points that are markedly different from those of alpha-bisabolol, and can be separated by simple distillation. With this method, product mixtures containing alpha-bisabolol can be achieved with farnesol contents below 0.5%.
The selective esterification of farnesol is achieved, according to DE 10 2005 026 768, by reaction of the farnesol contained in the mixture with a nitrogen base and a benzoyl halide. The corresponding farnesyl benzoates are formed selectively, and can be separated in a simple distillation step.
In US 2010/0222606 A1 (WO 2007/082847), the problem of separating farnesol and alpha-bisabolol is also solved by esterification of the farnesol. The method is characterized in particular in that no wastewater is formed. The farnesyl carboxylic acid esters formed as coupling product can be used e.g. in fragrance applications, or in an alternative step they can be converted by saponification to farnesol. In this case, however, process wastewater is formed. The resultant farnesol can be used as educt for producing alpha-bisabolol.